Short-Wavelength Light Sensitivity of Circadian, Pupillary, and Visual Awareness in Humans Lacking an Outer Retina

Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College London, London W6 8RF, United Kingdom.
Current Biology (Impact Factor: 9.57). 01/2008; 17(24):2122-8. DOI: 10.1016/j.cub.2007.11.034
Source: PubMed


As the ear has dual functions for audition and balance, the eye has a dual role in detecting light for a wide range of behavioral and physiological functions separate from sight. These responses are driven primarily by stimulation of photosensitive retinal ganglion cells (pRGCs) that are most sensitive to short-wavelength ( approximately 480 nm) blue light and remain functional in the absence of rods and cones. We examined the spectral sensitivity of non-image-forming responses in two profoundly blind subjects lacking functional rods and cones (one male, 56 yr old; one female, 87 yr old). In the male subject, we found that short-wavelength light preferentially suppressed melatonin, reset the circadian pacemaker, and directly enhanced alertness compared to 555 nm exposure, which is the peak sensitivity of the photopic visual system. In an action spectrum for pupillary constriction, the female subject exhibited a peak spectral sensitivity (lambda(max)) of 480 nm, matching that of the pRGCs but not that of the rods and cones. This subject was also able to correctly report a threshold short-wavelength stimulus ( approximately 480 nm) but not other wavelengths. Collectively these data show that pRGCs contribute to both circadian physiology and rudimentary visual awareness in humans and challenge the assumption that rod- and cone-based photoreception mediate all "visual" responses to light.

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    • "IpRGCs project to brain areas associated with non-imageforming functions, such as the SCN for circadian photoentrainment (Hattar et al., 2003; Ruby et al., 2002) and the olivary pretectal nucleus (OPN) for controlling pupil size (Clarke, Zhang, & Gamlin, 2003; Hattar et al., 2002; Lucas et al., 2003). IpRGCs also project to the LGN (Berson, 2003; Dacey et al., 2005) and may contribute to image-forming processes (Barrionuevo & Cao, 2014; Brown et al., 2012; Horiguchi, Winawer, Dougherty, & Wandell, 2013; Zaidi et al., 2007). "
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    ABSTRACT: Intrinsically photosensitive retinal ganglion cells (ipRGCs) can respond to light directly through self-contained photopigment, melanopsin. IpRGCs also receive inputs from rods and cones. Thus, studying ipRGC functions requires a novel photostimulating method that can account for all of the photoreceptor inputs. Here, we introduce an inexpensive LED-based five-primary photostimulator that can control the excitations of rods, S-, M-, L-cones and melanopsin-containing ipRGCs in humans at constant background photoreceptor excitation levels, a critical requirement for studying the adaptation behavior of ipRGCs with rod, cone or melanopsin input. We describe the theory and technical aspects (including optics, electronics, software and calibration) of the five-primary photostimulator. Then we present two preliminary studies using the photostimulator we have implemented to measure melanopsin-mediated pupil responses and temporal contrast sensitivity function (TCSF). The results showed that the S-cone input to pupil responses was antagonistic to the L-, M- or melanopsin inputs, consistent with an S-OFF and (L+M)-ON response property of primate ipRGCs (Dacey et al., 2005). In addition, the melanopsin-mediated TCSF had a distinctive pattern compared with L+M or S-cone mediated TCSF. Other than control individual photoreceptor excitation independently, the five-primary photostimulator has the flexibility in presenting stimuli modulating any combination of photoreceptor excitations, which allows to study the mechanisms by which ipRGCs combine various photoreceptor inputs.
    • "These potential associations deserve more attention because diseases associated with progressive degeneration of certain areas of the eye could predict the risk of a patient developing a highly disruptive circadian rhythm sleep disorder and would provide guidance to physicians in the identification and treatment of circadian rhythm sleep disorders among the blind. Such considerations would also be important prior to elective enucleation of the eyes in case the eyes are still functional to detect light for circadian entrainment, even in the absence of vision, as has been previously demonstrated (Zaidi et al., 2007). "
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    ABSTRACT: Light is the major environmental time cue that synchronizes the endogenous central circadian pacemaker, located in the suprachiasmatic nuclei of the hypothalamus, and is detected exclusively by the eyes primarily via specialized non-rod, non-cone ganglion cell photoreceptors. Consequently, most blind people with no perception of light (NPL) have either nonentrained or abnormally phased circadian rhythms due to this inability to detect light. Conversely, most visually impaired participants with some degree of light perception (LP) exhibit normal entrainment, emphasizing the functional separation of visual and "nonvisual" photoreception. The aims of the study were to identify the prevalence of circadian disorders in blind women, with the further aim of examining how eye disease may relate to the type of circadian disorder. Participants (n = 127, age 50.8 ± 13.4 years) completed an 8-week field study including daily sleep diaries and sequential 4 to 8 hourly urine collections over 48 h on 2 to 3 occasions separated by at least 2 weeks. Circadian type was determined from the timing and time course of the melatonin rhythm measured by cosinor-derived urinary 6-sulfatoxymelatonin rhythm peak. Of the participants with NPL (n = 41), the majority were abnormally phased (24%) or nonentrained (39%), with 37% classified as normally entrained. Of the participants with LP (n = 86), the majority were normally entrained (69%). Eighteen LP participants (21%) were abnormally phased (8 advanced, 10 delayed). Nine LP participants (10%) were nonentrained. The eye conditions most associated with abnormal phase and/or nonentrained circadian rhythms were bilateral enucleation (67%) and retinopathy of prematurity (57%). By contrast, 84% of participants with retinitis pigmentosa and 83% of those with age-related macular degeneration were normally entrained. These findings suggest that the etiology of blindness in addition to LP status is related to an individual's ability to process the circadian light signal.
    Journal of Biological Rhythms 06/2014; 29(3):215-224. DOI:10.1177/0748730414536852 · 2.77 Impact Factor
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    • "The recent progress in understanding how light changes are unconsciously captured and transmitted to the circadian system (Benarroch, 2011; Foster and Hankins, 2007; Hatori and Panda, 2010) may someday help to explain the solar insolation findings in this study. Photosensitive retinal ganglion cells (pRGC) containing the pigment melanopsin mediate a broad range of non-image forming functions including circadian synchronization, melatonin suppression and alertness (Berson, 2003, Gooley et al., 2003; Zaidi et al., 2007). The intrinsic photosensitivity of pRGC is specialized to detect fluctuations in intensity of environmental light (Berson, 2003, Hatori and Panda, 2010) and the signals are sent to the circadian pacemaker in the suprachiasmatic nucleus (SCN). "
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    ABSTRACT: BACKGROUND: The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode. METHODS: Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations. RESULTS: There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduced by half if there was no family history. The maximum monthly increase in solar insolation occurred in springtime. The effect was one-third smaller for initial episodes of mania than depression. The largest maximum monthly increase in solar insolation occurred in northern latitudes such as Oslo, Norway, and warm and dry areas such as Los Angeles, California. LIMITATIONS: Recall bias for onset and family history data. CONCLUSIONS: A large springtime increase in sunlight may have an important influence on the onset of bipolar disorder, especially in those with a family history of mood disorders.
    Journal of Affective Disorders 05/2014; 167C. DOI:10.1016/j.jad.2014.05.032 · 3.38 Impact Factor
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